This letter describes the results of a Food and Drug Administration (FDA) inspection that concluded on September 29, 2008. The FDA investigators met with you and other members of your staff to review BioReliance Corporation’s conduct of nonclinical laboratory studies (b)(4) and (b)(4) performed under the Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies regulations [Title 21, Code of Federal Regulations, (CFR) Part 58]. The inspection was conducted as part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to review research involving investigational products.

At the end of the inspection a Form FDA 483, Inspectional Observations, was issued and discussed with you and other BioReliance staff. We received and reviewed your October 28 Letter responding to the Form FDA 483, addressed to the FDA Baltimore District Director.

Based upon the information obtained during the inspection and your October 28 Letter, we conclude that BioReliance has violated GLP regulations governing the proper conduct of nonclinical studies as published under 21 CFR Part 58. The applicable provisions of the CFR are cited for each violation.

1. Failure of the study director to assure that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred and corrective action was taken and documented. [21 CFR § 58.33(c)]. Failure of the quality assurance unit (QAU) to determine that no deviations from approved standard operating procedures (SOPs) were made without proper authorization and documentation. [21 CFR § 58.35(b)(5)]. Failure to conduct nonclinical laboratory studies in accordance with the protocol. [21 CFR § 58.130(a)].

Your firm did not check every animal cage for feed and water each day, or clean the animal cages for study (b)(4) for twelve days. The protocol-specified interval for cleaning cages is (b)(4). As a result, the animals were not checked (b)(4) as required in the “Animal Care Schedule” SOP OPBT0206.R06. BioReliance animal care staff noted on the “Clinical Observation Record for In Vivo Biologics Assays” that four animals were found dead and others “hunched, possibly due to lack of food in cage.” Other animals were found dead and partially cannibalized, or found dead and sent to necropsy. The (b)(4) body weight charts showed 38% of the study animals lost an average of more than of 10% of their body weight during the period from November 17 to November 28, 2006; another 15% of the animals lost an average of 5% to 10% of body weight. The Animal Room Logs showed the animals had food and water, but the Cage Changing Log shows that cleaning had not been performed. This discrepancy raises the possibility that causes other than the absence of food and water could have contributed to the weight loss. There was no documented tracking of study animals to specific animal rooms, and it is not possible to determine what other GLP studies took place in the room where dead and hunched animals were found.

A. The (b)(4) Study Director did not investigate these circumstances. There was no deviation report to document the lack of animal cage sanitation, and no report was made to the study sponsor. The “Event Details Report” was re-opened during the FDA inspection and a document entitled “Corrective/Preventative Actions” was prepared during the inspection.

B. The QAU failed to generate a deviation report or to initiate an investigation into the circumstances of these events. Your firm’s investigation took place more than one year after these events occurred, in response to an FDA inquiry regarding the final study report.

Your October 28 Letter explains that BioReliance considers these deviations to be an isolated event with no significant impact on integrity of the study or study validity criteria. The Letter further explains that the final study report was eventually amended to include results and conclusions from your investigation of these events. You report that BioReliance performed required cage changes for (b)(4) GLP studies that were queried during the FDA inspection using a master schedule for studies that took place from November 2007 to June 2008. It is not possible to determine the accuracy of your statement that this was an isolated event because of the lack of documentation and also conflicting information regarding this incident at BioReliance. No study director or QAU investigations took place and no deviation report was generated within a year of the incident. These events demonstrate that the study director was either not informed about the unforeseen loss of animal weight, or did not act to investigate. Animal husbandry records for this study are in disagreement concerning the accomplishment of animal feeding and cage cleaning. As a result it is not possible to determine what happened in this study or to assess the extent of the problems.

Cage cleaning and sanitizing deficiencies were also noted during your previous FDA inspection which ended on October 20, 2005. You also report that the BioReliance laboratory staff was retrained concerning use of specific forms and SOPs, including the “Animal Room Log,” “Cage Changing Log,” “Recording of Data” SOP, “Abbreviations Used in Error Corrections on Documents Supporting GxP Operations” SOP, and the “Animal Care Schedule” SOP. Form FMDC0332 was revised to require confirmation of cage change performance at a minimum of (b)(4).

2. Failure to ensure that each individual engaged in the conduct of, or responsible for the supervision of a nonclinical laboratory study has the education, training, and experience or combination thereof to enable that individual to perform their assigned functions. [21 CFR § 58.29(a)].

The QAU failed to detect and report that the study director was overdue for GLP training, as required by BioReliance SOPs OPBT0290 section 5.3 and ODTD2001 section 5.4. The study director for studies (b)(4) and (b)(4) did not participate in GLP training at least every (b)(4), as required in BioReliance SOP OPDL0052 section 5.3. The Director’s GLP training deficiency occurred during the same period as the deficiencies for the studies noted in this letter.

The October 28 Letter states that this individual has more than 20 years of experience as a GLP study director, and your firm does not believe a GLP refresher-training gap of 5 months compromised GLP compliance for studies (b)(4) and (b)(4). During the inspection BioReliance gave the FDA investigators a flow chart showing a training notification system currently under development.

3. Failure to prepare a final nonclinical laboratory study report that included a description of all circumstances that may have affected the quality or integrity of the data. [21 CFR § 58.185(a)(9)].

A. There is no description in the (b)(4) final study report of BioReliance’s animal husbandry lapses described in item 1, above. These deficiencies introduced a variable into the test system whose potential effects on the outcome of the GLP study cannot not be determined.

Your letter explains that BioReliance reported to the sponsor unforeseen circumstances relating to lack of food, including study animal clinical observations and weight data, during the conduct of the study as well as within the study report. There is no documentation showing BioReliance reported its failure to sanitize mouse cages to the sponsor. The FDA investigators were furnished an e-mail that shows the sponsor asked BioReliance for information concerning deaths of study animals. The FDA investigators requested documentation showing that BioReliance reported its failure to sanitize mouse cages at appropriate intervals to the sponsor, but you have not provided the documentation to FDA.

B. There was no documentation to track specific study room locations for (b)(4) and (b)(4) study animals. The lack of such documentation makes a definitive evaluation of the environmental, animal husbandry, and room sanitation conditions impossible.

During the inspection your firm revised the “Cage Changing Log” to document the room where the study animals are housed.

C. BioReliance did not report discrepant clinical observations involving palpable lesions noted on the “Palpation Records” for 23 of the (b)(4) mice in the (b)(4) high dose group. Prosectors found only one animal in this group with a nodule at the site of inoculation on gross examination. This discrepancy was not included in the final pathology report, as required by the study protocol in which "the pathologist is required to summarize all the findings (clinical, gross and microscopic) for the test and control groups and present them to the study sponsor at the end of the study."

Your letter does not address this inspectional observation.

We are also concerned about the following issues, which the FDA investigators discussed with you at the close of the inspection:

A. BioReliance does not track specific room locations of test animals in the in vivobiologics testing area.

B. Study documents and verbal statements conflict regarding the (b)(4) for the inspected studies’ test and control articles. The BioReliance Director of Quality Systems and Quality Assurance Manager both stated that the (b)(4) was “(b)(4),” not (b)(4) as noted throughout the inspection and specified in the protocols. (b)(4) is not listed as a component or an (b)(4) in the test article preparation documentation or the corresponding final study reports for the protocols.

C. BioReliance (b)(4) under the inspected protocols, and the (b)(4) mice. Neither the protocols nor the BioReliance SOPs required (b)(4). During the inspection, BioReliance furnished the FDA investigators a listing of (b)(4) other GLP studies involving the (b)(4), in which, according to BioReliance, (b)(4) testing were not performed. During the inspection, BioReliance furnished the FDA investigators with a revised SOP to include measurement of (b)(4). At the close of the inspection, the FDA investigators requested documentation for any (b)(4) characterization for the (b)(4) studies.

The deviations listed above are not intended to be an all-inclusive list of GLP deficiencies that may exist at your testing facility. As a GLP-testing facility, you are responsible for ensuring that you conduct nonclinical studies according to FDA regulations.

This Warning Letter is issued to you because of the serious nature of the observations noted at the time of the FDA inspection. Please be advised that failure to implement effective corrective actions and/or commission of further violations may result in the FDA taking regulatory action without further notice.

Within fifteen (15) working days of receiving this letter, please provide written documentation of the additional actions you have taken or will take, to correct the above violations and prevent the recurrence of similar violations in current or future nonclinical studies.

Please send your written documentation to:

Anthony D. Hawkins

Division of Inspections and Surveillance (HFM-664)

Office of Compliance and Biologics Quality

Center for Biologics Evaluation and Research

1401 Rockville Pike, Suite 200N

Rockville, Maryland 20852-1448

Telephone (301) 827-6338

We request that you send a copy of your response to the FDA District Office listed below.